Solved protein puzzle opens door to new design for cancer drugs

July 12, 2018, Oregon State University
Credit: CC0 Public Domain

Researchers at Oregon State University have solved a longstanding puzzle concerning the design of molecular motors, paving the way toward new cancer therapies.

Findings were published today in Current Biology.

The research involved kinesins: tiny, protein-based motors that interact with microtubules inside . The motors convert chemical energy into mechanical energy to generate the directional movements and forces necessary to sustain life.

Microtubules are microscopic tubular structures that have two distinct ends: a fast-growing plus end and a slow-growing minus ends. Microtubules help make up a cell's skeleton.

Most kinesins only interact with just one , but a subgroup of kinesins called -14s preferentially bind to two different microtubules: one with the protein's feet, and one with its tail.

Scientists had known little about what drives that preference, but researchers in the OSU College of Science revealed that some kinesin-14s have a stiff rather than a flexible waist separating the feet from the tail—that's the reason these motor proteins prefer a two-microtubule track.

The findings are important because certain cancer cells depend on kinesin-14 to proliferate, and now there's way to halt those cells: with drugs that make that stiff waist more elastic, thus grinding the molecular motor to a halt and killing the cell.

"Kinesin-14s contribute to the assembly of an oval-shaped superstructure called the spindle," said the study's corresponding author Weihong Qiu, assistant professor of physics at OSU. "The spindle functions to ensure chromosomes are accurately separated between daughter cells during cell division."

Qiu and collaborators at the College of Science, Henan University and Nankai University in China, and the University of Michigan looked at kinesin-14s from two sources: a fungus and a fruit fly.

"We cut open the waist part to insert a flexible polypeptide linker," Qiu said.

The results were dramatic. The fungal kinesin-14 motor changed its direction, moving toward the minus end of the microtubules rather than the plus end, and the fly's kinesin-14 motor shifted from being non-processive—i.e., it would only step one way, then the other—to also being a processive, minus-end-directed motor.

But the ability of the fruit fly kinesin-14 to bind to two microtubules was severely compromised by having a flexible waist rather than a stiff one.

"Nature through evolution came up with a remarkable plan in terms of the design of the motor protein," Qiu said. "Most kinesin-14 motors function inside the spindle and need to interact with two different microtubules rather than one. Our research reveals that to accommodate that functional need, these kinesin-14s have evolved to have a rigid middle piece."

Altering that design via drug intervention would kill cancer cells that rely on kinesin-14 to spread.

"Our results imply a novel therapeutic approach, which is to target the waist region of the motor protein," Qiu said. "If the kinesin-14 motor can bend at the waist like a gymnast, then its ability to interact with two microtubules is lost, and so is its function. Now drugs can be identified that modify the rigidity of the waist region."

Explore further: Molecular motor mystery solved: Novel protein rounds out plant cells' machinery

More information: Current Biology (2018). DOI: 10.1016/j.cub.2018.05.026

Related Stories

Molecular motor grows cell's microtubules

October 26, 2015

Motor proteins that pause at the ends of microtubules and produce pushing forces can also stimulate their growth, according to researchers at Penn State. The proteins' function could be a critical component in understanding ...

The motor protein dancing in all our cells

September 26, 2017

Motor proteins drive many of the essential processes in our cells. They move with a dancing motion, as Professor Erik Schäffer and his team have shown in a new study. In order to observe the tiny proteins, which are measured ...

Experiments show hypothesis of microtubule steering accurate

January 23, 2014

Tiny protein motors in cells can steer microtubules in the right direction through branching nerve cell structures, according to Penn State researchers who used laboratory experiments to test a model of how these cellular ...

Recommended for you

Orangutan mothers found to engage in displaced reference

November 15, 2018

A pair of researchers with the University of St Andrews has observed orangutan mothers engaging in displaced reference after observation of a perceived threat. In their paper published in the journal Science Advances, Adriano ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.